This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Decoy Receptor 3 (DcR3) is a secreted immunosuppressive protein that belongs to the Tumor Necrosis Factor (TNF) receptor superfamily. Its overexpression has been closely linked to cancer and autoimmune diseases. The dissection of DcR3's functional mechanism is complicated by its ability to neutralize three different TNF ligands: FasL, LIGHT, and TL1A. Each of these ligands binds distinct functional receptors, resulting in unique immune responses. Defining the interactions between DcR3 and its ligands may provide new therapeutic opportunities to a variety of human diseases, including rheumatoid arthritis, Chron's disease and malignancies. Here, we report the crystal structures of unliganded DcR3 and the DcR3-TL1A complex. These structures show that TL1A adopts a tight homotrimeric organization and that DcR3 is an elongated soluble receptor with novel cysteine-rich-domain module architecture. Each DcR3 molecule binds the groove between two adjacent TL1A subunits, resulting in a 3:3 stoichiometry. This structural information, in combination with complementary mutagenesis and biochemical characterization, reveals a mode of receptor recognition distinct from other TNF family members. This study explains the structural basis of DcR3 as a generic decoy receptor that neutralizes multiple ligands and provides insight into the functional annotation of the immunological network involving DcR3.